Biodegradable polymers are a large and growing segment of the medical device market, and have found varying applications for use. They are predominantly used in sutures, but have also found use in orthopedic fixation devices such as interference screws in the ankle, knee, and hand areas; as tacks and pins for ligament attachment and meniscal repair; as suture anchors; and as rods and pins for fracture fixation.
Biodegradable polymers have also found use in at least two dental applications. Employed as a void filler following tooth extraction, porous polymer particles can be packed into the cavity to aid in quicker healing. As a guided-tissue-regeneration (GTR) membrane, films of biodegradable polymer can be positioned to exclude epithelial migration following periodontal surgery. The exclusion of epithelial cells allows the supporting, slower-growing tissue—including connective and ligament cells—to proliferate. Three examples of these GTR materials are Resolut™ from W. L. Gore (Flagstaff, Ariz.) (a poly(dl-lactide-co-glycolide) (PGA-DLPLA) polymer), Atrisorb™ from Atrix Laboratories (Fort Collins, Colo.) (a poly(dl-lactide) (DLPLA) polymer) and Vicryl™ mesh from Ethicon (a poly(l-lactide-co-glycolide) (PGA-LPLA) polymer).
Poloxamers and their use have a long history. Chemically, they are non-ionic, triblock copolymers of the following general structure:
The structure consists of a hydrophobic central core of propylene oxide (represented by “b” in the above figure), flanked by hydrophilic ethylene oxide (represented by “a” in the above figure) on both sides. Poloxamers are soluble in water and other polar and non-polar solvents and are regarded as chemically inert. Commercially, poloxamers are available from BASF as flakes (denoted by “F”), paste (denoted by “P”), liquid (denoted by “L”) and micronized (denoted by “micro”). Their chemical composition and specifications are provided below in Tables 1 and 2.
TABLE 1Content ofOxyethylenePluronic ®Poloxamerab(Percent)Molecular WeightL 44 NF124122044.8-48.62090-2360F 68 NF188802779.9-83.77680-9510F 87 NF237643770.5-74.36840-8830F 108 NF3381414481.4-84.912700-17400F 127 NF4071015671.5-74.9 9840-14600
TABLE 2Poloxamer124188237338407Physical FormLiquidSolidSolidSolidSolidpH (2.5% in5.0-7.55.0-7.55.0-7.55.0-7.55.0-7.5water)Cloud point,71-75° C.>100° C.>100° C.>100° C.>100° C.10%APHA color50 max.100 max.100 max.100 max.120 max.% H2O0.4 max.Cast solid 0.4Cast solid 0.4Cast solid 0.4Cast solid 0.4max.max.max.max.Prill 0.75 max.Prill 0.75 max.Prill 0.75 max.Prill 0.75 max.BHT, ppm—50-12550-12550-12550-125Unsaturation0.020 ± 0.0080.026 ± 0.0080.034 ± 0.0080.031 ± 0.0080.048 ± 0.017mEq/gEthylene1 max.1 max.1 max.1 max.1 max.Oxide, ppmPropylene5 max.5 max.5 max.5 max.5 max.Oxide, ppm1,4 dioxane,0.002% max.0.002% max.0.002% max.0.002% max.0.002% max.ppm
Poloxamers show temperature dependent thermoreversible properties. Poloxamer 407 (F127) is the most well studied poloxamer for this behavior. Generally, this behavior has been studied in 20-30% w/w aqueous solutions, which are liquid at low temperature (2-5° C.) and turn into gel at room temperature (22-25° C.). This gelation temperature is dependent on the molecular weight and the percentage of the hydrophobic portion, hence the gelling temperature decreases as both the molecular weight and the hydrophobic fraction increases. In general, the gelation temperature increases in the order of F127<F108<F87<F68<F44. The gelation temperature can also be modulated by varying the percentage of F127, or mixing it with one or more other poloxamers. The three pharmaceutically relevant (due to availability and approved for use in pharmaceutical products) poloxamers are F127, F108, and F68.
Despite all of their interesting and useful physical properties, poloxamer gelled matrices have not been developed that can serve as a drug eluting implant, and that meet demanding requirements such as controlled drug release, controlled erosion, metabolic clearance, viscosity at room temperature, and adhesion to biological surfaces. The aim of this work was to develop a poloxamer formulation that could meet these demanding requirements, and function as a completely biocompatible and bioerodible drug delivery implant.